Regulation of macrophage apoptosis by anthrax lethal factor The inhalation form of Bacillus anthracis is an aggressive pathogen and is an ideal weapon for bioterrorism. After phagocytosis by alveolar macrophages, the anthrax spores germinate to become vegetative bacteria. Infected macrophages migrate to regional lymph nodes and die, but fail to kill the intracellular bacteria. Patients rapidly succumb to the massive septicemia and toxemia. Macrophage death is an essential component in the associated pathology, as macrophage-depleted animals are resistant to the Lethal affects of anthrax toxin. We propose experiments to investigate the signal transduction pathways contributing to macrophage responses, macrophage death, and to the subsequent death of the host. These experiments will be conducted in cultured human macrophage cell lines and lavaged macrophages obtained from healthy donor lungs. Additionally, we will use a novel in vitro organ culture model of human lung described in the technology development section. We will test the role of MEK cleavage and the contribution of TNFalpha signal transduction to the macrophage cell death. Lastly, we will investigate differences in macrophage responses following concomitant exposure to both B. anthracis toxins, a situation that likely occurs in vivo.